Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0085580 (essential hypertension)
 14,686 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Atrial natriuretic factor (ANF) might be beneficial in several cardiovascular disorders, but its poor oral absorption and rapid inactivation in vivo have so far prevented its use in therapeutics. We have assessed the role of enkephalinase (membrane metallo-endopeptidase, EC 3.4.24.11) in the in vivo inactivation of ANF in mice and healthy human volunteers by evaluating the effects of acetorphan, a potent inhibitor. In mice, the degradation of 125I-labeled ANF was markedly delayed, as shown by the levels of the intact peptide in the plasma and the kidney, a major target organ. The effect of acetorphan was due to the inhibition of enkephalinase activity, since it occurred at an ED50 very close to this drug's ID50 for the inhibition of the specific binding of radioactive material to the kidney or lung peptidase that was measured after administration of [3H]acetorphan. The effects of acetorphan were also studied in eight healthy human volunteers by using a randomized double-blind, placebo-controlled design. Oral administration of acetorphan elicited a lasting elevation of plasma ANF-like immunoreactivity, with a time course parallel to that of the inhibition of plasma enkephalinase activity. These effects were accompanied by significant increases in urinary volume and sodium excretion, two well-established renal responses to ANF peptides. These results indicate that enkephalinase plays a critical role in ANF degradation in vivo and that its inhibition enhances the levels of circulating endogenous ANF, which, in turn, results in diuresis and natriuresis. Enkephalinase inhibition may constitute another therapeutic approach to the treatment of cardiovascular diseases, such as congestive heart failure or essential hypertension, on which ANF is postulated to have a beneficial effect.
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PMID:Protection of atrial natriuretic factor against degradation: diuretic and natriuretic responses after in vivo inhibition of enkephalinase (EC 3.4.24.11) by acetorphan. 252 43

Due to its physiological and pharmacological action ANF could be an ideal diuretic and vasorelaxation product in the treatment of oedema and essential hypertension. Experimental and clinical investigations in oedematous conditions revealed a very slight diuretic and natriuretic effect of ANF, as compared with healthy subjects. This is due to the reduced renal perfusion pressure, the increased RAAS activity, enzymatic degradation of ANF by endopeptidase and also its inactivation via C-receptors. Moreover the use of ANF is very limited due to its short half-life and peptide structure. In recent years therefore new possibilities are sought how to influence the metabolism of endogenous ANF and thus increase its activity. Neutral endopeptidase inhibitors (NEP) inhibit ANF degradation, increase thus its plasma level and in cardiac weakntlakess have a marked diuretic and natriuretic effect. The administration of NEP inhibitors in patients with essential hypertension did not reveal so far an adequate effect on blood pressure. Inhibitors of C-receptors potentiate also the effect of endogenous ANF. In experiments they enhance Na excretion and lead to a drop of blood pressure. Recently another natriuretic peptide was detected--urodilatine. In experimental and clinical studies in cardiac failure urodilatine administration leads to an increase of diuresis and natriuresis greater than after ANF. Haemodynamic effects after urodilatine are also greater than after ANF whereby urodilatine does not cause reflex tachycardia and is resistant to peptidase degradation. Its therapeutic administration is a new perspective in the treatment of oedematous conditions and essential hypertension.
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PMID:[Use of natriuretic peptides in clinical practice]. 818 76